2-hydroxy-2-(methylsulfonyl)-acetophenone acetates and related compounds

ABSTRACT

In the above formula, R1 and R2 represent hydrogen, lower alkyl, lower alkoxy, aryl, and halogen, or R1 and R2 taken together with the benzene ring may form an additional aromatic or heteroaromatic nucleus.   Compounds of the formula I are disclosed:

United States Patent [19] Cohen et al.

[451 Jan. 21, 1975 2-HYDROXY-2-(METHYLSULFONYL)- ACETOPHENONE ACETATES AND RELATED COMPOUNDS ['75] Inventors: Marvin P. Cohen, New Milford;

Max Von Strandtmann, Rockaway,

[21] Appl. No.: 359,823

[52] US. Cl. 260/479 R, 260/287 R, 260/592.

424/311, 424/337 [51] Int. Cl. C07c 147/10, C076 147/06 [58] Field of Search 260/479 R, 592

[56] References Cited UNITED STATES PATENTS 3,345,416 10/1967 Russell et al 260/590 Primary Examiner-James A. Patten v Attorney, Agent, or FirmAlbert H. Graddis; Frank S. 'Chow [57] ABSTRACT Compounds of the formula 1 are disclosed:

R1 11 II In the above formula, R and R represent hydrogen, lower alkyl, lower alkoxy, aryl, and halogen, or R, and R taken together with the benzene ring may form an additional aromatic or heteroaromatic nucleus.

17 Claims, No Drawings 2-HYDROXY-2-METHYLSULFONYL)- ACETOPHENONE ACETATES AND RELATED COMPOUNDS The present invention relates to novel compounds and, more particularly, the present invention relates to compounds of the formula I:

dcrn l cm o con. R2 II wherein R and R taken together with the benzene ring, form an additional aromatic or heteroaromatic nucleus.

In the above definitions for R. and R the term lower alkyl" and the alkyl portions of alkoxy are meant to have one to six carbon atoms. These are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like. The term aryl" denotes an aromatic hydrocarbon having six to carbon atoms such as phenyl or tolyl. The term halogen encompasses fluorine, bromine, chlorine and iodine. The additional aromatic or heteroaromatic nucleus denotes such as naphthalene. isoquinoline, quinoline, and the like.

The compounds ofthis invention are useful gastric antisecretory agents. At the dose level of mg/kg intraperitoneally these compounds cause a 50-60% decrease in the volume of gastric acid in the rat, when tested according to the method described by Shay. et al. in Gasrroemerulogy 5, 43 i945) and Winter. et al., in Proc. Soc. Exper. Biol. and Meals, l 1 1,544 (i960).

These compounds are indicated in the management of gastric hyperacidity such as gastric ulcer in mammals. In human beings, for example, a dose of 20 mg/kg orally or by injection two or three times daily is recommended. This dose regimen can be varied depending on the severity of the condition, age and sex of the patient being treated by methods known to the healing arts.

In addition, those compounds wherein R is hydrogen and R is methyl or wherein R and R taken together with the benzene ring form a naphthalene ring system. at the dose level of 100 mg/kg administered intraperitoneally exhibit the property of suppressing selectively the delayed hypersensitivity immunological response in mice. The primary immunological response is not affected, which leaves the vital anti-infective defense mechanisms unimparied.

The test procedures involved are described by Jerne, et al.. in Cell-bound Antibodies, Wistar Institute Press 1963, p. 109. Thus. these compounds may be useful in conditions associated with delayed hypersensitivity states such as arthritis.

in order to use these compounds, they are combined with excipients such as lactose, and formulated into dosage forms such as tablets by known pharmaceutical technology. They are also formulated into dosage forms with excipients such as water for inject-ion suitable for parenteral administration.

According to the present invention, compounds of type I are prepared by the acetylation of compounds of type ll according to the following sequence:

2 R I i dcrnsour l 011 0 0 0 0 R1 [L g R1 IL 1,]

t.cu, cu. ccrn on. L crncoho i l OH occn R2 RE n 3 The starting materials II are synthesized by the oxidation of compounds of type III which are described .in our copending Pat. application Ser. No. 174,947, entitled "Substituted o-hydroxymethylsulfinylacetophenones and Related Compounds. Generally speaking, the oxidation step is effected at ambient temperature and the product is recovered: by conventional means. The step involving treatment of the product with acetic anhydride is also effected at ambient temperature and again the product is recovered by conventional means.

ln order to further illustrate the practice of this invention, the following examples are included. Temperatures referred to therein are given in degrees Centigrade.

EXAMPLE I 2-Hydroxy-2-(methylsulfonyl)-3'- phenylacetophenone A mixture of 16 g. of 2-hydroxy-2-(methylsulfinyl)- 3-phenylacetophenone. 300 ml. of CHCI and 13 g. of m-chloroperbenzoic acid was stirred for one-half hr. The temperature rose to The solution was gently boiled for one-half hr., chilled. and stirred with 100 ml. of saturated NaHCO solution. The organicphase was separated, dried over Na SO and evaporated to an oil under reduced pressure. On cooling the oil crystallized. and was recrystallized from abs. ethanol; m.p. 144-l45.5; yield 14 g. (83%);

Anal. Calcd. for C H O S: C, 62.05; H, 4.86; S, l 1.04. Found: C, 61.79; H, 4.98; S, 11.13.

EXAMPLE 2 o o L CH.(%CH.

OFECHJ 3-Hydroxy-2-(methylsulfonyl)-2T-acetonaphthone acetate A mixture of IO g. of 3'-hydroxy2-(methylsulfinyl)- 2-acetonaphthone, ml. of acetic anhydride, and 0.5 ml. of pyridine was stirred for 2 hr. The mixturewas poured into 800 ml. of ice water and the mixture was stirred for 1 hr. The precipitated solid was filtered off, washed with cold water, and recrystallized from CH CN; m.p. l62164; yield 7.0 g. (60 /1);

Anal. Calcd. for C, -,H O S: C, 58.81; H, 4.61; S, 10.47. Found: 59.06; H, 4.90; S, 10.70.

EXAMPLE 3 O O ikCHa EXAMPLE 4 IIQ O EXAMPLE 5 0 CII2 1L CH:

0 2-Hydroxy-5 '-methyl-2-(methylsulfonyl )acetophenone acetate A mixture of 10 g. of 2'-hydroxy-5-methyl-2- (met-hylsulfonyl)acetophenone, 50 ml. of acetic anhydride and 0.5 ml. of pyridine was stirred for 1.5 hr. The solution was poured into 800 m1. of ice water, and the mixture was stirred for 1 hr. The precipitated solid was filtered off, washed with cold water and recrystallized from methanol; m.p. 104.5-105.5; yield 5.5 g (46%) Anal. Calcd for C H O S: C, 53.32; H, 5.22; 5, 11.86. Found: C, 53.47; H, 5.22; 5, 11.76.

EXAMPLE 6 3'-Chloro-2-hydroxy-2-(methylsulfonyl)acetophenone A mixture of 50 g. of 3'-ch1oro-2'-hydroxy-2- (methylsulfinyl)acetophenone, 1.5 1. ol'CHCl and 50 g. of m-chloroperbenzoic acid was stirred for one-half hr. The temperature rose to 50. The mixture was gently boiled for one-half hr.. chilled. and stirred for 10 min. with 300 ml. of saturated NaHCO solution. The organic phase was separated and evaporated to a solid under reduced pressure. This was recrystallized from abs. ethanol; m.p. 124.5125.5; yield 50 g. (96%) Anal. Calcd. for C,,H,,C10.,S: C, 43.47; H, 3.65; S, 12.89. Found: C, 43.33; H, 3.67; S, 12.85.

EXAMPLE 7 O 0 1% CH; 01 0 3-Chloro-2-hydroxy-2-( methylsulfonyl )acetophenone acetate A mixture of 10 g. of 3-chloro-2"hydroxy-2- (methylsulfonyl)acetophenone, 50 ml. of acetic anhydride and 0.5 m1. of pyridine was stirred for 1 hr. The solution was poured onto 800 ml. of ice water and the mixture was stirred for 1 hr. The precipitate was filtered off, washed with cold water. and recrystallized from CH CN; m.p. 154158; yield 9.5 g. (82%); A max mp. (e) 225 (24,000), 298 (5,200); 11 max 805 (ms), 920 (m), 1030 (m), 1135 (ms), 1190 (ms), 1210 (s), 1695 (ms), 1760 (s) cm.

Anal. Calcd for C H CIO S: C, 45.45; H, 3.81; C1,

12.19; S, 11.03. Found: C, 45.51; H, 3.89; CI, 12.04; S, 10.95.

EXAMPLE 8 o Jicm -oufl 2 -Hydroxy-3 -methoxy-2-( methylsulfonyl )acetophenone A mixture of 30 g. of 2'-hydroxy-3'-methoxy-2- (methylsulfinyl)acetophenone, 750 m1. of CHCl,-;, and 33 g. of m-chloroperbenzoic acid was stirred for onehalf hr. The temperature rose to 50. The solution was boiled gently for one-half hr., chilled, and stirred 10 min. with 200 m1. of saturated NaHCO solution. The organic phase was separated, and the aqueous phase extracted three times with 50 m1. portions of CHCl Combined organic phase and extracts were evaporated to a solid residue under reduced pressure. The residue was recrystallized from abs. ethanol; m.p. 142-143; yield 24 g. (74%); A max mp. (e) 220 (16,000), 270 (9,300), 343 (2,400); 11 max 735 (m), 780 (m), 840 (m), 970 (m), 1015 (ms), 1140 (m), 1255 (s), 1620 (ms) cm". 5

Anal. Calcd. for C H Q S: C, 49.17; H, 4.95; S, 13.13. Found: C, 49.43; H, 4.99; S, 13.02

EXAMPLE 9 OCCII:

2'-Hydroxy-3-methoxy-2-(methylsulfonyl)acetophenone acetate To a mixture of 10 g. of 2-hydroxy-3- methoxy-2-(methylsulfonyl)acetophenone and 50 ml. of acetic anhydride was added several drops of pyridine and the mixture was stirred. After one-half hr. a clear solution formed, and after 1 hr. a crystalline precipitate deposited. The mixture was poured into 800 ml. of ice water, and the mixture was stirred for 1 hr. The mixture was filtered, and the precipitate was recrystallized from methanol; m.p. 106107; yield 9 g. (77%); A max m .t (e) 227(20,600), 251 (11,600), 305 (4,000); 11 max 790 (ms), 920 (m). 1005 (ms), 1125 (s), 1185 (ms). 121011115). 1280(ms), 1295 (s), 1590(m), 1700(ms), 1760 (s) cm".

Anal. Calcd lor C H SO C, 50.34; H, 4.93; S,

11.20. Found: C, 50.37; H, 5.02; S, 11.26.

EXAMPLE 10 1'-Hydroxy-2-(methylsulfonyl)2'-acetonaphthone A mixture of g. of 1'-hydroxy-2-(methylsulfony1)- 2-acetonaphthone, 1.5 l. of CHC1 and 50 g. of mchloroperbenzoic acid was stirred for one-half hr. The temperature rose to 45. The mixture was gently boiled for one-halfhr., chilled and stirred for 10 min. with 300 ml. of saturated NaHCO solution. The organic phase was separated and evaporated to a crystalline residue under reduced pressure. The residue was recrystallized from abs. ethanol; m.p. l59-16l; yield 44 g. (83%); A max mu (6) 217 (27,300), 260 (31,100), 287 (7,100), 298 (9,100), 309 (5,750), 385 (5,800); 11 max 805 (ms), 905 (m), 975 (ms), 1045 (ms), 1160 (ms), 1270 (ms), 1615 (ms) cm".

Anal. Calcd. for C, -,H, O,S: C, 59.08; H, 4.58; S, 12.13. Found: C, 59.03; H, 4.64; S, 12.29.

EXAMPLE 1 l O Ol JCHa 60 o -CCII E-Clh 1 1. ll

1-Hydroxy-2-(methylsullonyl)-2-acetonztphthonc acetate A mixture of 10g. of 1'-hydroxy-2-(methylsull'onyl)- 2-acetonaphthone, 50 ml. of acetic anhydride, and 0.5 ml. of pyridine was stirred for 1 hr. The resulting paste was stirred with 800 ml. of ice water for 1 hr., and the precipitated solid was filtered off, washed with cold water and recrystallized from ethyl acetate; m.p. I37-139; yield 8.5 g. (73%); A max mp. (e) 218 (38,500), 252 (27.200), 297 (5,700), 327 (3,900), 341 (4,200); 11 max 790 (m), 830 (ms), 910 (m), 1045 (ms). 1160 (ms), 1210 (s), 1690 (ms), 1760 (s). cm.

Anal. Calcd for C,,,H O,-,S: C, 58.81; H, 4.61; 5. 10.47. Found: C. 58.89; H. 4.65; S, 10.50.

EXAMPLE I2 5-Fluoro-2'-hydroxy-2-(methylsulfonyl)acetophenone A mixture of 27 g. of 5'-fluoro-2-hydroxy-2(methylsulfinyl)acetophenone, 1.5 l. ofCHCI and 30 g. of mchloroperbenzoic acid was stirred for one-halt hr. The temperature rose to 45. The solution was gently boiled for one-half hr., chilled, and stirred for 10 min. with 200 ml. of saturated NaHCO solution. The organic phase was separated and evaporated to a solid under reduced pressure. The solid was recrystallized from abs. ethanol; m.p. 120.5122.5; yield 25 g. (86% A max my. (6) 255 (7,450); 357 (4,300); 11 max 750 (m), 745 (ms), 840 (m), 975 (m), 1140 (s). 1195 (s), 1230 (ms), 1625 (ms); 1640 (ms) cm"..

Anal. Calcd. for C H FO S: C, 46.55; H, 3.91; S, 13.81. Found: C, 46.74; H, 4.03; S, 13.90.

EXAMPLE I3 O CH2 CH3 F 11 5 -Fluoro-2 -hydroxy-2-( methylsulfonyl )acetophenone acetate To a mixture of 10 g. of 5'-fluoro-2-hydroxy-2- (methylsulfonyl)acetophenone and 50 m1. of acetic anhydride was added 0.5 ml. of pyridine, and the mixture was stirred for 1 hr. The resulting clear solution was poured into 800 m1. of ice water and the mixture was stirred for 1 hr. The precipitate was filtered off, washed with cold H 0, and recyrstallized from methanol; m.p. l16-118; yield 8 g. (68%); A max mu (6) 229 (14,300), 300 (5,300); vmax 855 (m), 885 (ms). 910 (s), 995 (ms), 1015 (m), 1120 (s), 1170 (s), 1190 (s), 1210 (s), 1590 (m), 1680 (ms), 1695 (ms), 1765 (s) cm.

Anal. Calcd for C, H FO,=,S: C, 48.17; H, 4.04; S, 11.69. Found: C, 48.25; H, 4.02; S, 11.67.

EXAMPLE 14 0 0 01m -licm%-om 7 2'-Hydroxy-3',5'-dimethyl-2-(methylsult'onyl- )acetophenone A mixture of 27 g. of 2'-hydroxy-3,5-dimethyl- 2(methylsulfinyl)acetophenone, 1500 ml. of CHClg, and 27 g. of m-chloroperbenzoic acid was stirred for one-half hr. The temperature rose to 45. The solution was gently boiled for one-half hr., cooled in an ice bath, and stirred for min. with 300 ml. of saturated NaH- CO solution. The organic phase was separated, and taken down to a crystalline residue under reduced pressure. The material was recrystallized from abs. ethanol; m.p. l"82-l84; yield 28 g. (96%); A max mp. (e) 216 (13,800), 271 (10,200), 363 (3,360); 1 max 825 (m), 1075 (m), 1170 (m), 1270 (m), 1635 (ms) cm".

Anal. Calcd. for C H O S: C, 54.53; H, 5.82. Found: C, 54.63; H, 6.05

EXAMPLE O O A 0113 CH3 0 0 2-Hydroxy-3,5-dimethyl-2-(methylsulfonyl- )acetophenone acetate A mixture oflO g. of 2'-hydroxy-3',5-dimethyl-2- (methylsulfonyl)acetophenone, 100 ml. of acetic anhydride and 0.5 ml. of pyridine was stirred for 18 hr. The clear solution was poured into 800 ml. of ice water, and the mixture was stirred for 1 hr. The precipitated was filtered off, washed with cold water, and recrystallized from methanol; m.p. ll3.5-1l5; yield 8 g. (69%); A max mp. (e) 232 (22,000), 308 (4,800); 11 max 920 (m), 1080 (ms), 1135 (ms), 1 170 (ms), 1210 (s), 1230 (s), 1690 (ms), 1745 (s), cm.

Anal. Calcd for C H O S: C, 54.92; H, 5.67. Found: c, 54.80; H, 5.69.

EXAMPLE 16 HO CH;

2-Hydroxy-3-methyl-2-(methylsulfonyl)acetophenone A mixture of 27 g. of 2'-hydroxy-3-methyl-2- (methylsulfinyl)acetophenone, 27 g. of mchloroperbenzoic acid and 600 ml. of CHCl was stirred for one-half hr. The temperature rose to 45. The mixture was gently boiled for one-half hr., chilled, and stirred for 10 min. with 200 ml. of saturated NaH- C0,, solution. The organic phase was separated and concentrated to an oil under reduced pressure. The oil was crystallized from abs. ethanol. The crystals were filtered and recrystallized from abs. ethanol; m.p. 100102; yield 24 g. (857:); A max my. (6) 214 (16,700), 268 1 1,400), 347 (3,500); V max 780 (ms), 980 (m), 1140 (ms), 1230 (m), 1620 (ms) cm.

Anal. Calcd. for C ,H, O.,S: C, 52.62; H, 5.30. 5, 14.05. Found: C. 52.36; H. 5.26; S, 14.31.

EXAMPLE 17 0 CHJJIIZO (I111:

2-Hydroxy-3'-methyl-2-(methylsulfonyl)acetophenone acetate A mixture of 10 g. of 2-hydroxy-3'-methyl-2- (methylsulfonyl)acetophenone, 50 ml. of acetic anhydride, and 0.5 ml. of pyridine was stirred for 1 hr. The solution was poured onto 800 ml. of ice water, and the mixture was stirred for 1 hr. The precipitate was filtered off, washed with cold water, and recrystallized from CH CN; m.p. l42-l47; yield 4 g. (3171); A max mp. (e) 226 (22,000), 297 (4,700); 11 max 800 (ms), 980 (m), 1075 (s), 1140 (s), 1195 (s), 1220 (s), 1685 (ms), 1745 (s) cm".

Anal. Calcd. for C H O S: C, 53.32; H, 5.22; S, 11.86. Found: C, 53.59 H, 5.10; S, 11.88.

EXAMPLE l8 3-Hydroxy-2-(methylsulfonyl)-2'-acetonaphthone A mixture of 40 g of 3-hydroxy 2-(methylsulfinyl)- 2-acetonaphthone, 1,500 ml ofCH- Cland 40 g of mchloroperbenzoic acid (Aldrich Chem.Co.) was stirred for 5 hr. The insoluble precipitate was filtered, and recrystallized from CH CN; mp 201203. yield 32 g Anal. Calcd for C H O S: C, 59.08; H, 4.58; S, 12.13. Found: C, 58.83; H, 4.52; S, 12.17.

EXAMPLE l9 CHaO HTCHzI ICHa 2'-Hydroxy-6-methoxy-2(methylsulfonyl)acetophenone A mixture of 10 g of 2'-hydroxy-6'-methoxy-2- (methylsulfinyl)acetophenone, 375 ml of CHCL', and 10 g of m-chloroperbenzoic acid (Aldrich Chem.Co) was stirred for one-half hr. The temperature rose to 45. The mixture was gently boiled for one-half hr, cooled to 25, and stirred for 10 min with ml of saturated NaHCO solution. The organic phase was separated, and evaporated to a solid residue under reduced pressure. The residue was recrystallized from absolute ethanol; mp l52.5155.5; yield 7 g (65%) Anal. Calcd for C H O S: C, 49.17; H, 4.95. Found: C, 49.00 H, 5.20.

hydroxy-2-(methylsulfonyl)-2-acetonaphthone EXAMPLE 20 4'-Chloro-2 '-hydroxy-2-( methylsulfonyl)acetophenone To a solution of 18 g of 4'-chloro-2'-hydroxy-2- (methylsulfinyl)acetophenone in 600 ml of CHCI was added 16.2 g of m-chloroperbenzoic acid (Aldrich Chem.Co.) with stirring. The temperature gradually rose to 37. The solution was stirred for 10 min, and then gently boiled for min, chilled, and stirred for 10 min with 200 ml of saturated NaHCO solution. The organic phase was separated, and evaporated to a crystalline residue under reduced pressure. The material was recrystallized from ethyl acetate; mp 15l.5153.5; yield 12 g (63%); max ma (6) 213 (17,700), 266 (13,000), 325 (4,800); 1 max 800 (m), 905 (m), 1080 (m), 1120 (m), 1155 (m), 1230 (m), 1620 (ms) cm.

Anal. Calcd for C,,H.,ClO S: C, 43.47; H, 3.65; S, 12.89; Found: C, 43.63; H, 3.65; 5, 13.16.

We claim:

1. A compound of the formula:

wherein R and R are hydrogen, lower alkyl having one to six carbon atoms, lower alkoxy having one to six carbon atoms. hydrocarbon aryl having six to 10 carbon atoms or halogen or R and R taken together with the benzene ring forming naphthalene.

2. A compound according to claim 1 which is 3'- acetate.

3. A compound according to claim 1 which is 2- hydroxy-6-methoxy-2-(methylsulfonyl)acctophcnonc acetate.

4. A compound according to claim 1 which is 2- hydroxy-S -methyl-2-( mcthylsull'onyl )acctophcnonc acetate.

5. A compound according to claim 1 which is 3- chloro-2-hydroxy-2-( mcthylsulfonyl )acctophcnonc acetate.

6. A compound according to claim 1 which is 2'- hydroxy-3 -methoxy-2-( methylsulfonyl )acctophcnonc acetate.

7. A compound according to claim 1 which is lhydroxy-2-(methylsulfonyl)-2-acetonaphthonc acctate.

8. A compound according to claim l-which is 5'- fluoro2'-hydroxy-2-(methylsulfonyl)acetophenonc acetate.

9. A compound according to claim 1 which is 2- hydroxy-3 ,5 -dimethyl-2-(methylsulfonyl )acetophenone acetate.

l0. A compound according to claim 1 which is 2'- hydroxy-3 '-methyl-2-( methylsulfonyl )acetophenonc acetate.

11. 3 -chloro-2'-hydroxy-2-( methylsultonyl- )acetophenone.

l2. 2 -hydroxy-3 -methoxy-2-( methylsullonyl- )acetophenone. 

2. A compound according to claim 1 which is 3''-hydroxy-2-(methylsulfonyl)-2''-acetonaphthone acetate.
 3. A compound according to claim 1 which is 2''-hydroxy-6''-methoxy-2-(methylsulfonyl)acetophenone acetate.
 4. A compound according to claim 1 which is 2-hydroxy-5''-methyl-2-(methylsulfonyl)acetophenone acetate.
 5. A compound according to claim 1 which is 3''-chloro-2''-hydroxy-2-(methylsulfonyl)acetophenone acetate.
 6. A compound according to claim 1 which is 2''-hydroxy-3''-methoxy-2-(methylsulfonyl)acetophenone acetate.
 7. A compound according to claim 1 which is 1''-hydroxy-2-(methylsulfonyl)-2''-acetonaphthone acetate.
 8. A compound according to claim 1 which is 5''-fluoro-2''-hydroxy-2-(methylsulfonyl)acetophenone acetate.
 9. A compound according to claim 1 which is 2''-hydroxy-3'',5''-dimethyl-2-(methylsulfonyl)acetophenone acetate.
 10. A compound according to claim 1 which is 2''-hydroxy-3''-methyl-2-(methylsulfonyl)acetophenone acetate.
 11. 3''-chloro-2''-hydroxy-2-(methylsulfonyl)acetophenone.
 12. 2''-hydroxy-3''-methoxy-2-(methylsulfonyl)acetophenone.
 13. 1''-hydroxy-2-(methylsulfonyl)2''-acetonaphthone.
 14. 5''-fluoro-2''-hydroxy-2-(methylsulfonyl)acetophenone.
 15. 3''-hydroxy-2-(methylsulfonyl)-2''-acetonaphthone.
 16. 2''-hydroxy-6''-methoxy-2-(methylsulfonyl)-acetophenone.
 17. 4''-chloro-2''-hydroxy-2-(methylsulfonyl)-acetophenone. 